Thyroid Hormone Receptor Agonists and Use Thereof

This application is a continuation of U.S. application Ser. No. 18/448,277, filed on Aug. 11, 2023, which is a continuation of U.S. application Ser. No. 17/147,538, filed on Jan. 13, 2021, now U.S. Pat. No. 11,780,825, which claims the benefit of and priority to International Application No. PCT/CN2020/071741, filed on Jan. 13, 2020, and International Application No. PCT/CN2020/107757, filed on Aug. 7, 2020, the entire contents of each of which are incorporated herein by reference in their entireties.

The contents of the electronic sequence listing (ECCO_003_C01US_SeqList_ST26.xml; Size: 6,355 bytes; and Date of Creation: Aug. 11, 2023) are herein incorporated by reference in their entirety.

Thyroid hormones are critical for normal growth and development and for maintaining metabolic homeostasis. Circulating levels of thyroid hormones are tightly regulated by feedback mechanisms in the hypothalamus/pituitary/thyroid (HPT) axis. Thyroid dysfunction leading to hypothyroidism or hyperthyroidism clearly demonstrates that thyroid hormones exert profound effects on cardiac function, body weight, metabolism, metabolic rate, body temperature, cholesterol level, maintenance of bone and muscle, and behavior. Thyroid hormones stimulate the metabolism of cholesterol to bile acids and enhance the lipolytic responses of fat cells to other hormones. Thyroid hormones also affect cardiac function. For example, tach, cardia, increased stroke volume, increased cardiac index, cardiac hypertrophy, decreased peripheral vascular resistance, and increased pulse pressure are observed in patients with hyperthyroidism.

The biological activity of thyroid hormones is mediated by thyroid hormone receptors (THRs). THRs form heterodimers with the retinoid receptor that act as ligand-inducible transcription factors THRs regulate gene expression through interactions with DNA response elements and various nuclear co-activators and co-repressors. The thyroid hormone receptors are derived from two separate genes, α and β. The major thyroid receptor isoforms are α1, α2, β1, and β2. The thyroid hormone receptor subtypes can differ in their contribution to particular biological responses. THRβ isoform are predominantly expressed in the brain and liver tissues, and are responsible for the feedback regulation of the HPT axis and the lipid lowering effect. THRα isoform selective activation is associated with the adverse effects in heart and bones. Accordingly, selective activation of the THRβ isoform in liver tissue is desirable.

Therapeutically beneficial effects of thyroid hormone include increasing metabolic rate, oxygen consumption, and heat production, and thereby reducing body weight, lowering LDL, and elevating HDL. Disorders of the thyroid are generally treated with hormone replacement, by administering either naturally occurring thyroid hormones or thyromimetic analogues which mimic the effects of thyroid hormones.

The development of thyroid hormone analogs which avoid the undesirable effects of hyperthyroidism and hypothyroidism while maintaining the beneficial effects of thyroid hormones would open new avenues of treatment for patients with metabolic diseases such as obesity, hyperlipidemia, hypercholesterolemia, diabetes, and other disorders and diseases such as liver steatosis and NASH, atherosclerosis, cardiovascular diseases, hypothyroidism, thyroid cancer, thyroid diseases, and related disorders and diseases. As such, there is a need for novel thyroid hormone analog compounds that have the beneficial effects of thyroid hormone while avoiding the undesirable effects. The present application addresses such a need.

The present application provides novel thyroid hormone receptor ligands which are useful in the treatment of a disease or disorder regulated by thyroid hormone, such as those described herein, including but not limited to obesity, overweight condition, hyperlipidemia (e.g., severe high triglyceride (SHTG), familial partial lipodystrophy(FPLD), familial chylomicronemia syndrome (FCS), xanthomas, familial dysbetalipoproteinemia/hypolipoproteinemia type III, hyperlipoproteinemia, sitosterolemia), sphingolipid metabolism diseases, thyroid disease (e.g., Hashimoto's disease, thyroiditis, thyroid dysgenesis, congenital hypothyroidism, inherited thyroid hormone binding protein abnormalities), hypothyroidism, thyroid cancer, and related disorders and diseases, such as nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver steatosis, liver fibrosis, hypercholesterernia, familial hypercholesterolemia (HeFH/HoFH), X-linked adrenoleukodystrophy (X-ALD), diabetes mellitus, atherosclerosis, hypertension, coronary heart disease, depression, osteoporosis, cardiac arrhythmias, glaucoma, congestive heart failure, and pancreatitis.

A first aspect of the application relates to a compound of Formula (I′) or (I):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein R, R, R, R, R, L, X, X, and Xare as described in detail below.

Another aspect of the application relates to a pharmaceutical composition comprising a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

Another aspect of the application relates to a method of treating a disease or disorder regulated by thyroid hormones, including but not limited to a liver disease, a metabolic disease, a thyroid disease, and a cardiovascular disease, such as the disease or disorder described herein. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

Another aspect of the application relates to a method of treating liver diseases. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

Another aspect of the application relates to a method of treating metabolic diseases. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

Another aspect of the application relates to a method of treating cardiovascular diseases. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

Another aspect of the application relates to a method of reducing fibrosis (e.g., liver fibrosis). The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

Another aspect of the application relates to a method of treating nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), liver steatosis, or liver fibrosis. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

Another aspect of the application relates to a method of treating atherosclerosis. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

Another aspect of the application relates to a method of treating stroke and complications thereof. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

Another aspect of the application relates to a method of treating myocardial infarction. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

Another aspect of the application relates to a method of modulating (e.g., activating) thyroid hormone receptors. The method comprises administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a therapeutically effective amount of a pharmaceutical composition comprising a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier.

Another aspect of the application relates to a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier, for use in a method of treating a disease or disorder regulated by thyroid hormones, as described herein.

Another aspect of the application relates to use of a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, or a pharmaceutical composition comprising a compound of Formula (I) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, and a pharmaceutically acceptable diluent, excipient, or carrier, in the manufacture of a medicament for treating a disease or disorder regulated by thyroid hormones, as described herein.

The present application further provides methods of treating a disease or disorder associated with modulation of thyroid hormone receptors including, but not limited to, liver diseases, metabolic diseases, cardiovascular diseases, fibrosis (e.g., liver fibrosis), NAFLD, NASH, liver steatosis, liver fibrosis, atherosclerosis, stroke and complications thereof, myocardial infarction, and other disease or disorder described herein, comprising administering to a subject suffering from at least one of the diseases or disorders a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

The present application provides compounds that are therapeutic agents in the treatment of diseases such as liver diseases (e.g., NAFLD and NASH), metabolic diseases, cardiovascular diseases, and other diseases associated with the modulation of thyroid hormone receptors.

The present application relates to compounds and compositions thereof that are capable of modulating the activity of thyroid hormone receptors. The application features methods of treating, preventing, or ameliorating a disease or disorder in which thyroid hormone plays a role by administering to a subject in need thereof a therapeutically effective amount of a compound of Formula (I′) or (I), or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof. The compounds of the present application can be used in the treatment of a variety of diseases and disorders regulated by thyroid hormones, such as those described herein, by modulating the activity of thyroid hormone receptors, including, but not limited to, liver diseases (e.g., NAFLD and NASH), metabolic diseases, cardiovascular diseases, and other diseases associated with the modulation of thyroid hormone receptors.

In a first aspect of the application, a compound of Formula (I′) or (I) is described:

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein:

In some embodiments, a compound of Formula (I′) or (I) is of Formula (Ia′) or (Ia):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

In some embodiments, a compound of Formula (I′) or (I) is of Formula (Ib′) or (Ib):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

In some embodiments, a compound of Formula (I′) or (I) is of Formula (Ic′) or (Ic):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof.

In one embodiment, for a compound of Formula (I′), (I), (Ia′), (Ia), (Ib′), (Ib), (Ic′), or (Ic), where applicable, X, X, X, L, R, R, R, R, R, R, R, R, R, R, R, R, R, and y are each as defined below.

In some embodiments, any group defined herein for any one of X, X, X, L, R, R, R, R, R, R, R, R, R, R, R, R, R, and y can be combined with any group defined herein for one or more of the remainder of X, X, X, L, R, R, R, R, R, R, R, R, R, R, R, R, R, and y.

In some embodiments, a compound of Formula (I′) or (I) is of any one of Formula (I1′), (I1), (I2′), (I2), (I3′), (I3), (I4′), (I4), (I5′), (I5), (I6′), (I6), (I7′), (I7), (I8′), or (I8):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L, R, R, R, R, R, R, R, R, R, R, and y are each as defined herein, and any group defined herein for any one of L, R, R, R, R, R, R, R, R, R, R, R, and y can be combined with any group defined herein for one or more of the remainder of L, R, R, R, R, R, R, R, R, R, R, R, and y, for example, where applicable, as in (A1)-(N7).

In some embodiments, a compound of Formula (I′) or (I) is of any one of Formula (I1a′), (I1a), (I2a′), (I2a), (I3a′), (I3a), (I4a′), (I4a), (I5a′), (I5a), (I6a′), (I6a), (I7a′), (I7a), (I8a′), or (I8a):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L, R, R, R, R, R, R, R, R, R, and y are each as defined herein, and any group defined herein for any one of L, R, R, R, R, R, R, R, R, R, and y can be combined with any group defined herein for one or more of the remainder of L, R, R, R, R, R, R, R, R, R, and y, for example, where applicable, as in (A1)-(N7).

In some embodiments, a compound of Formula (I′) or (I) is of any one of Formula (I1b′), (I1b), (I2b′), (I2b), (I3b′), (I3b), (I4b′), (I4b), (I5b′), (I5b), (I6b′), (I6b), (I7b′), (I7b), (I8b′), or (I8b):

or a pharmaceutically acceptable salt, solvate, prodrug, stereoisomer, or tautomer thereof, wherein L, R, R, R, R, R, R, R, R, R, R, and y are each as defined herein, and any group defined herein for any one of L, R, R, R, R, R, R, R, R, R, R, and y can be combined with any group defined herein for one or more of the remainder of L, R, R, R, RR, R, R, R, R, R, and y, for example, where applicable, as in (A1)-(N7).

In some embodiments, a compound of Formula (I′) or (I) is of any one of Formula (I1c′), (I1c), (I2c′), (I2c), (I3c′), (I3c), (I4c′), (I4c), (I5c′), (I5c), (I6c′), (I6c), (I7c′), (I7c), (I8c′), or (I8c):